Fidanacogene elaparvovec

Experience with use of fidanacogene elaparvovec in patients receiving hepatotoxic medicinal product or using hepatotoxic substances is limited. Care should be exercised when administering potential hepatotoxic medicinal substances, herbal supplements, and alcohol to patients treated with fidanacogene elaparvovec, as the efficacy of fidanacogene elaparvovec may be reduced, and the risk of serious hepatic reactions may increase following fidanacogene elaparvovec administration.

Prior to fidanacogene elaparvovec administration, the patient’s existing concomitant medicinal products should be reviewed to determine if they should be modified to prevent possible anticipated interactions. After fidanacogene elaparvovec administration, patients' concomitant medications should be monitored particularly during the first year, and the need to change concomitant medicinal products based on patients' hepatic health status and risk should be evaluated. When a new medication is started, close monitoring of ALT and factor IX activity levels (e.g., weekly to every 2 weeks for the first month) is recommended to assess potential effects on both levels.

No immunocompromised patients, including patients undergoing immunosuppressive treatment within 30 days before fidanacogene elaparvovec infusion, were enrolled in clinical studies with fidanacogene elaparvovec.

Safety and efficacy of this medicinal product in these patients have not been established. Use in immunocompromised patients is based on healthcare professional’s judgement, taking into account the patient’s general health and potential for corticosteroid use post-fidanacogene elaparvovec treatment.

Medicinal products that may reduce or increase the plasma concentration of corticosteroids (e.g., medicinal products that induce or inhibit cytochrome P450 3A4) can decrease the efficacy of the corticosteroid regimen or increase their side effects.

No dose adjustment is needed in patients with renal impairment. The safety and efficacy of fidanacogene elaparvovec have not been studied in patients with clinically relevant renal impairment (creatinine >2.0 mg/dL).

The safety and efficacy of fidanacogene elaparvovec in patients with severe hepatic impairment have not been studied. Fidanacogene elaparvovec is not recommended for use in patients with other significant hepatobiliary disorders.

Pre-treatment evaluation of hepatobiliary condition

Pre-treatment evaluation of hepatobiliary condition should confirm the absence of clinically significant hepatobiliary disease, as defined by any of the below:

• alanine transaminase (ALT), aspartate transaminase (AST), or alkaline phosphatase (ALP) levels >2 × upper limit of normal (ULN), bearing in mind that at least 2 readings may be required to interpret variability over time (at most within 4 weeks)
• bilirubin >1.5 × ULN (at most within 4 weeks)
• current liver-related coagulopathy, hypoalbuminemia, persistent jaundice, cirrhosis, active viral hepatitis
• history of portal hypertension, splenomegaly, or hepatic encephalopathy
• negative fibrosis assessment (at most 3 months before infusion)

In case of radiological liver abnormalities and/or sustained liver enzyme elevations, consideration of a consultation with a hepatologist is recommended to assess eligibility for fidanacogene elaparvovec administration.

In patients with haemophilia B with pre-existing risk factors for thromboembolic events, such as a history of cardiovascular or cardiometabolic disease, arteriosclerosis, hypertension, diabetes, advanced age, the potential risk of thrombogenicity may be higher after treatment.

Patients should be evaluated before and after administration of fidanacogene elaparvovec for risk factors for thrombosis and general cardiovascular risk factors. Based on factor IX activity levels achieved, patients should be advised according to their individual condition. Patients should seek immediate medical attention if they observe signs or symptoms that may indicate a thrombotic event.

As there is a theoretical risk of malignant transformation leading to cancer resulting from AAV-mediated integration into the host cell DNA, considerations should be given to regular long-term follow-up monitoring (see long-term follow-up).

It is recommended that patients with pre-existing risk factors for hepatocellular carcinoma (such as hepatic fibrosis, hepatitis C or B disease, non-alcoholic fatty liver disease) undergo regular liver ultrasound screenings and are regularly monitored for alpha-fetoprotein (AFP) elevations on a yearly basis for at least 5 years after fidanacogene elaparvovec administration.

In the event that a malignancy occurs, the marketing authorisation holder should be contacted by the treating healthcare professional to obtain instructions on collecting patient samples for potential vector integration examination and integration site analysis.

Experience regarding the use of this medicinal product during pregnancy is not available. Animal reproduction studies have not been conducted. Fidanacogene elaparvovec is not recommended during pregnancy.

It is unknown whether fidanacogene elaparvovec is excreted in human milk. A risk to the newborns/infants cannot be excluded. Fidanacogene elaparvovec should not be used during breast-feeding.

Women of childbearing potential

No dedicated animal fertility/embryofoetal studies have been conducted to substantiate whether the use in women of childbearing potential and during pregnancy could be harmful for the newborn child (theoretical risk of viral vector integration in foetal cells through vertical transmission). Moreover, no data are available to recommend a specific duration of contraceptive measures in women of childbearing potential. Therefore, fidanacogene elaparvovec is not recommended in women of childbearing potential.

Contraception after administration to males

For 6 months after administration of fidanacogene elaparvovec, treated patients of reproductive potential and their female partners of childbearing potential must prevent or postpone pregnancy using barrier contraception and avoid contact with semen. Males treated with fidanacogene elaparvovec must not donate semen to minimise the potential risk of paternal germline transmission.

Fertility

No information is available on the effects of fidanacogene elaparvovec on female or male fertility.

Infusion of fidanacogene elaparvovec may have a minor influence on the ability to drive and use machines. Because of potential adverse reactions such as headaches and dizziness that have occurred shortly after fidanacogene elaparvovec administration, patients should be advised to use caution when driving and operating machinery until they are certain that this medicinal product does not adversely affect them.

Summary of the safety profile

The most frequently reported adverse reaction following administration was transaminases increased (43.3%).

Tabulated list of adverse reactions

The safety of fidanacogene elaparvovec was evaluated in 60 patients who received the recommended dose (5 × 10¹¹ vector genomes/kg) in 2 open-label clinical studies. The adverse reactions identified with fidanacogene elaparvovec are presented in Table 1.

Adverse reactions are classified according to MedDRA system organ classification and frequency. Frequency categories are derived according to the following conventions: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Tabulated list of adverse reactions to fidanacogene elaparvovec:

^* Includes terms alanine transaminase (ALT) increased, aspartate transaminase (AST) increased, hepatic enzyme increased, hepatic function abnormal, liver function test abnormal, transaminases increased.
^** Includes abdominal pain and epigastric pain.

Description of selected adverse reactions

Hepatic laboratory abnormalities

Forty-three of the 60 (71.7%) patients had ALT elevations and 44 of the 60 (73.3%) patients had AST elevations. Thirty-seven of the 60 (61.7%) patients with ALT elevations also experienced AST elevations. The median onset time of first ALT elevation was 39 days (range: 2 to 2186 days) and the median time to resolution of the first ALT elevation was 13 days (range: 4 to 1373 days). All ALT elevation episodes (52/52) from all participants (36/36) that started within 120 days of fidanacogene elaparvovec infusion resolved. Thirty-one participants had 58 ALT elevation episodes post day 120, and 83% of the episodes had resolved at the time of data cut. Of those unresolved only 3 patients remained > ULN.

Thirty-one out of 60 (51.7%) patients received corticosteroids. The mean time to corticosteroid initiation was 46 days. The mean duration of corticosteroid treatment was 112 days (range: 41 to 276 days). Among those who received corticosteroids (n=31), no patients experienced Grade 3 or above ALT or bilirubin elevations as shown in Table 2 below.

Table 2. Number (%) of patients with ALT or bilirubin elevation and shift in elevation grade between before corticosteroid initiation and post-cessation of corticosteroid treatment:

^* Participants who received corticosteroids.
^ The last ALT and bilirubin ALT liver enzyme results prior to the initiation of corticosteroid treatment.
^& The peak ALT and bilirubin ALT liver enzyme results post-cessation of corticosteroid treatment.
CTCAE grades for ALT elevation: Grade 1: > ULN to 3.0 × ULN if baseline was normal; 1.5 to 3.0 × baseline if baseline was abnormal. Grade 2: > 3.0 to 5.0 × ULN if baseline was normal; > 3.0 to 5.0 × baseline if baseline was abnormal. Grade 3: > 5.0 to 20.0 × ULN if baseline was normal; > 5.0 to 20.0 × baseline if baseline was abnormal. Grade 4: > 20.0 × ULN if baseline was normal; > 20.0 × baseline if baseline was abnormal.
CTCAE grades for bilirubin elevation: Grade 1: > ULN to 1.5 × ULN if baseline was normal; 1.0 to 1.5 × baseline if baseline was abnormal; Grade 2: > 1.5 to 3.0 × ULN if baseline was normal; > 1.5 to 3.0 × baseline if baseline was abnormal; Grade 3: > 3.0 to 10.0 × ULN if baseline was normal; > 3.0 to 10.0 × baseline if baseline was abnormal; Grade 4: > 10.0 × ULN if baseline was normal; > 10.0 × baseline if baseline was abnormal.

Immunogenicity

The administration of fidanacogene elaparvovec has the potential to generate immunity in the form of neutralising antibodies against the vector capsid, the transgene (viral-derived factor IX) and as a cellular response against the transduced cells producing factor IX.

No patients developed factor IX inhibitors during the clinical studies using fidanacogene elaparvovec. There are currently no data regarding the efficacy of fidanacogene elaparvovec when used in patients with history of factor IX inhibitors.

A sustained increase in neutralising anti-AAVRh74var antibodies has been observed after administration of fidanacogene elaparvovec in all subjects who participated in clinical studies and had neutralising antibody assessment. In the Phase 3 clinical study, the mean neutralising anti-AAVRh74var antibodies titre value at week 52 was 28 531.10 and remained generally elevated at week 156 assessment.

Fidanacogene elaparvovec-treated patients were tested for cellular immune responses to overall capsid pool and overall factor IX pool using an IFN-γ ELISpot assay. ELISpot results did not show a trend of presumed T-cell response (based on positive ELISpot) as a function of time during the 1-year post-infusion period in either the Phase 3 or Phase ½ clinical studies.